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Titolo:
TOTAL SYNTHESIS OF CYCLOISODITYROSINE, RA-VII, DEOXYBOUVARDIN, AND N29-DESMETHYL-RA-VII - IDENTIFICATION OF THE PHARMACOPHORE AND REVERSAL OF THE SUBUNIT FUNCTIONAL ROLES
Autore:
BOGER DL; YOHANNES D; ZHOU JC; PATANE MA;
Indirizzi:
SCRIPPS CLIN & RES INST,DEPT CHEM,10666 N TORREY PINES RD LA JOLLA CA92037 PURDUE UNIV,DEPT CHEM W LAFAYETTE IN 47907 PURDUE UNIV,DEPT MED CHEM W LAFAYETTE IN 47907
Titolo Testata:
Journal of the American Chemical Society
fascicolo: 9, volume: 115, anno: 1993,
pagine: 3420 - 3430
SICI:
0002-7863(1993)115:9<3420:TSOCRD>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANTITUMOR CYCLIC HEXAPEPTIDES; CELL-WALL GLYCOPROTEIN; RUBIAE RADIX; CONFORMATIONAL-ANALYSIS; DIARYL ETHERS; AMINO-ACIDS; BOUVARDIN; MACROCYCLIZATION; PEPTIDES; ANALOG;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
73
Recensione:
Indirizzi per estratti:
Citazione:
D.L. Boger et al., "TOTAL SYNTHESIS OF CYCLOISODITYROSINE, RA-VII, DEOXYBOUVARDIN, AND N29-DESMETHYL-RA-VII - IDENTIFICATION OF THE PHARMACOPHORE AND REVERSAL OF THE SUBUNIT FUNCTIONAL ROLES", Journal of the American Chemical Society, 115(9), 1993, pp. 3420-3430

Abstract

Full details of a concise total synthesis of RA-VII (1) and deoxybouvardin (2) are described based on the implementation of an effective intramolecular Ullmann reaction as the key macrocyclization reaction in the preparation of the elusive 14-membered cycloisodityrosine subunit (33) of the bicyclic hexapeptides. Subsequent coupling of 34 to tetrapeptide 17 and macrocyclization with C2-N3 amide bond formation provided 1 and 2. In efforts that address the key structural and conformational features of the agents that contribute to their antitumor activity,N29-desmethyl-RA-VII was prepared and its chemical, conformational, and preliminary biological properties are detailed. The comparable conformational features of N29-desmethyl-RA-VII and RA-VII including a characteristic cis C30-N29 amide bond suggest that the tetrapeptide housed within the 18-membered ring induces the 14-membered cycloisodityrosine to adopt a conformation possessing an inherently disfavored cis secondary or tertiary amide. Moreover, in contrast to prior suppositions in which the rigid 14-membered ring of N-methylcycloisodityrosine has been suggested to serve the functional role of inducing a rigid, normally inaccessible conformation within the biologically relevant D-Ala-Ala-N-Me-Tyr-(OMe)-Ala tetrapeptide, experimental studies demonstratingthat the intrinsic activity of the agents resides within the cycloisodityrosine subunit are presented. Thus, the results of the experimental studies require a reversal of the functional roles of the subunits of the agents in which it is the tetrapeptide housed within the 18-membered ring that potentiates the inherent biological properties and alters the conformation of cycloisodityrosine.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/09/20 alle ore 22:11:21